The present invention relates to compositions and methods for preventing, treating or diagnosing cancers. In particular, it provides novel peptides capable of binding major histocompatibility complex (MHC) molecules and inducing an immune response against selected tumor cells.
The immune system has the ability to mount responses that can destroy tumor cells. Among the various elements of the immune system, cytotoxic T lymphocytes (CTL) are likely the most effective in mediating the rejection of established tumors. This is because CTL recognize antigenic determinants produced from any protein synthesized within the cell, while antibodies recognize and bind only integral cell surface molecules.
The anti-tumor activity of tumor-specific CTL is the result of a series of complex molecular events, More specifically, after cellular processing of proteins in the cytoplasm of the tumor cells, small peptides are transported to the endoplasmic reticulum, where they bind to newly synthesized major histocompatibility gene complex (MHC) class I molecules. MHC/peptide complexes are then exported to the surface of the tumor cell, where they are recognized by antigen-specific Class I-restricted CTL. In addition to lysing the tumor cell, the CTL may also secrete lymphokines such as tumor necrosis factor (TNF), and gamma-interferon (.gamma.-IFN), which also contribute to the overall anti-tumor effect.
Mutations of genes encoding cellular proteins (such as oncogenes), and/or the overexpression of genes coding for regulatory proteins (such as, tumor suppressor proteins) can result in the production of potential tumor-specific immunogenic peptides. A family of approximately 12 genes of yet undefined function (called MAGE, for "melanoma antigen") have been described, some of which are selectively expressed in a variety of human malignant cells (particularly in melanomas), but not in most normal tissues, with the exception of the testis (WO 92/20356). For example, the MAGE-1 gene is expressed in approximately 40% of melanomas and in some other tumors. A recent report has described the isolation from a melanoma patient of CTL specific for a 9 residue peptide (EADPTGHSY) (SEQ ID NO.:1), derived from the processing of the MAGE-1 protein (van der Bruggen, et al. (1991) Science 254:1643-1647). Evidence also shows that the CTL recognize the MAGE-1-derived peptide in the context of the HLA-A1 molecule (Traversari et al. (1992) J. Exp. Med. 176:1453-457).
In contrast with the somewhat limited frequency of expression of MAGE-1, the MAGE-2 and MAGE-3 genes are expressed in approximately 80-90% of the melanoma lines examined, and also in the other tumor types such as breast, colon, lung and thyroid cancers (Zakut et al. (1990) Cancer Res. 53:5-8). Thus, it would be attractive to identify peptides derived from the MAGE-2 or MAGE-3 gene products which could serve as CTL antigens.
Despite the developments in the art, the prior art has yet to provide a useful human peptide-based vaccine or therapeutic agent based on this work. The present invention provides these and other advantages.